Population genetics of transgenes in mosquito vectors

描述（由申请方提供）：昆虫品系经过基因工程改造，繁殖能力降低，无法传播致病病原体。具有这些性状的昆虫预计不会通过自然选择的直接作用取代天然昆虫基因型，因此需要开发将迫使这些转基因进入天然昆虫种群的遗传驱动机制。一些潜在的战略，使用特定的驱动机制进行了讨论，初步的人口遗传模型已经开发，以评估某些战略的可行性。在这些评估中有许多差距。拟议的研究将开发一个全面的建模框架，可用于确定最有可能成功抑制特定地区特定虫媒疾病的转基因方法。一个主要的重点将是建立一个空间明确的随机模型的矢量人口动态和遗传学。该模型将与疾病流行病学模型相结合。第一个模型将被设计为适合埃及伊蚊和登革热病毒（DV）的生物学。许多相关的生物学参数的估计可从以前和正在进行的研究。其他参数将从所提出的实验中估计，所述实验将测量预期与转基因插入相关的适应性成本，以及加载的转座子的基因组内移动的模式。具体的转基因操作，将被检查：1）插入条件致死等位基因，2）插入雌性特异性致死等位基因，3）工程欠显性，4）插入加载自主转座子，5）感染转基因沃尔巴克氏体菌株。使用新的转基因操作的潜力将与更一般的模型进行检查。建模工作的结果将预测，根据目前的生物数据，DV抑制策略预计将在特定的环境条件下取得成功。研究结果还将表明，未来的实证研究工作应该集中在哪里，以获得更精确和准确的估计关键的生物学参数为Ae。埃及人。 将举办跨学科讲习班，以确保最终制定的模型框架足够灵活，可供从事疟疾和其他虫媒疾病研究的研究人员使用。将编制一份方便用户的模型和一份可查阅的手册，并将其放在互联网上。

DESCRIPTION (provided by the applicant): Insect strains have been genetically engineered for decreased capacity to reproduce and for inability to transmit disease-causing pathogens. Insects with such traits are not expected to replace native insect genotypes through the direct action of natural selection so there is a need to develop genetic drive mechanisms that will force these transgenes into native insect populations. A number of potential strategies for using specific drive mechanisms have been discussed, and preliminary population genetic models have been developed to assess the feasibility of certain strategies. There are numerous gaps in these assessments. The proposed research will develop a comprehensive modeling framework that can be used in determining the transgenic approaches that are most likely to successfully suppress specific insect-borne diseases in specific regions. A major focus will be the building of a spatially explicit stochastic model of vector population dynamics and genetics. This model will be coupled to models of disease epidemiology. The first model will be designed to fit the biology of Aedes aegypti and dengue virus (DV). Estimates of many relevant biological parameters are available from previous and ongoing research. Other parameters will be estimated from proposed experiments that will measure the fitness costs expected to be associated with insertion of transgenes, and the pattern of intra-genomic movement of loaded transposons. Specific transgenic manipulations that will be examined are: 1) insertion of conditional lethal alleles, 2) insertion of female-specific lethality alleles 3) engineered underdominance, 4) insertion of loaded autonomous transposons, 5) infection with transgenic Wolbachia strains. The potential for using novel transgenic manipulations will be examined with more general models. Results of the modeling work will predict, based on current biological data, which DV suppression strategies are expected to succeed under specific environmental conditions. The results will also indicate where future empirical research efforts should be focused to gain more precise and accurate estimates of critical biological parameters for Ae. aegypti. Interdisciplinary workshops will be held to ensure that the final model framework developed is flexible enough to be used by researchers working with malaria and other insect-borne diseases. A user-friendly form of the models as well as an accessible manual will be developed and placed on the internet.